Journal article
UV irradiation remodels the specificity landscape of transcription factors
Proceedings of the National Academy of Sciences - PNAS, Vol.120(11), e2217422120
03/14/2023
DOI: 10.1073/pnas.2217422120
PMCID: PMC10089200
PMID: 36888663
Abstract
Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hypermutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all the TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs, we identified a surprising but reproducible effect at certain nonconsensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and nonconsensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.
Details
- Title: Subtitle
- UV irradiation remodels the specificity landscape of transcription factors
- Creators
- Zachery Mielko - Duke UniversityYuning Zhang - Duke UniversityHarshit Sahay - Duke UniversityYiling Liu - Duke UniversityMatthew A Schaich - University of PittsburghBrittani Schnable - UPMC Hillman Cancer CenterAbigail M Morrison - University of IowaDebbie Burdinski - McGovern Institute for Brain ResearchSheera Adar - Hebrew University of JerusalemMiles Pufall - University of Iowa, Biochemistry and Molecular BiologyBennett Van Houten - UPMC Hillman Cancer CenterRaluca Gordân - Duke UniversityAriel Afek - Weizmann Institute of Science
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.120(11), e2217422120
- Publisher
- PNAS
- DOI
- 10.1073/pnas.2217422120
- PMID
- 36888663
- PMCID
- PMC10089200
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- BSF-2019272 / United States - Israel Binational Science Foundation (BSF) R01 GM135658 / NIGMS NIH HHS R35 ES031638 / NIEHS NIH HHS
- Language
- English
- Date published
- 03/14/2023
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984473217802771
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